CN103910737B - 1,4-dihydropyran (2,3-c) pyrazole derivatives of chirality and synthetic method thereof and application - Google Patents

1,4-dihydropyran (2,3-c) pyrazole derivatives of chirality and synthetic method thereof and application Download PDF

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CN103910737B
CN103910737B CN201410115142.2A CN201410115142A CN103910737B CN 103910737 B CN103910737 B CN 103910737B CN 201410115142 A CN201410115142 A CN 201410115142A CN 103910737 B CN103910737 B CN 103910737B
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dihydropyran
chirality
pyrazole derivatives
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CN103910737A (en
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谢建武
孙平
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Huizhou Tuo Kang biological technology Co., Ltd.
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Zhejiang Normal University CJNU
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
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    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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Abstract

The invention discloses the 1 of a kind of chirality, 4 dihydropyran (2,3 c) pyrazole derivatives and synthetic method thereof and application, its synthetic method includes: with toluene as solvent, under Takemoto catalyst, substituted or unsubstituted pyrazolone derivative and Cyanoacetyl-Cyacetazid being reacted, product is post-treated obtains the 1 of chirality, 4 dihydropyran (2,3 c) pyrazole derivatives.The advantages such as the method has flexible reaction time, and yield is higher, easy and simple to handle, applied widely.1,4 dihydropyran (2,3 c) pyrazole derivatives of chirality of the present invention has the effect of suppression to gram positive bacteria and gram negative bacteria.

Description

1,4-dihydropyran (2,3-c) pyrazole derivatives of chirality and synthetic method thereof and Application
Technical field
The invention belongs to synthesis medicine, chemical field, relate generally to the synthetic method of a kind of heterocyclic compound, particularly to 1,4-dihydropyran (2,3-c) pyrazole derivatives of a kind of chirality with antibacterial activity and synthetic method thereof and application.
Background technology
Polysubstituted dihydropyran [2,3-c] pyrazole compound is the heterocyclic compound that a class is important, and they have necessarily Potential medicinal function, such as: antiinflammatory (Zaki, M.E.A.;Saliman,H.A.;Hickal,O.A.;Rashad, A.E.Z.Naturforsch.,C:Biosci.2006,61,1;Sheng,C.K.;Li,J.H.;Hideo, N.J.Med.Chem.1984,27,539.), antibacterial (Smith, W.P.;Sollis,L.S.;Howes,D.P.;Cherry, C.P.;Starkey,D.I.;Cobley,N.K.J.Med.Chem.1998,41,787;Mazaahir,K.;Shilpi,S.; Khalilur,R.K.;Sharanjit,S.T.Bioorg.Med.Chem.Lett.2005,15,4295.), anticancer (Wang, J.L.;Liu,D.;Zheng,Z.J.;Shan,S.;Han,X.;Srinivasula,S.M.;Croce,C.M.;Alnemri, E.S.;Huang,Z.Proc.Natl.Acad.Sci.U.S.A.2009,97,7124；Zaki,M.E.A.;Morsy,E.M.; Abdul,M.Heterocycl.Commun.2004,10,97.), suppress Ch1 kinases (Foloppe, N.;Fisher,L.M.; Howes,R.;Potter,A.;Robertson,A.G.S.;Surgenor,A.E.Bioorg.Med.Chem.2006,14, 4792) etc. it can also be used to biodegradable pesticide (Foloppe, N.;Fisher,L.M.;Howes,R.;Potter,A.; Robertson,A.G.S.;Surgenor, A.E.Bioorg.Med.Chem.2006,14,4792.) aspect is also a class simultaneously Important organic synthesis intermediate (Junek, H.;Aigner,H.Chem.Ber.1973,106,914;(b)Wamhoff,H.; Kroth,E.;Strauch, K.Synthesis.11,1129.), thus their synthesis is exactly organic chemists all the time A focus.
The method synthesizing polysubstituted dihydropyran [2,3-c] pyrazole compound is typically with Cyanoacetyl-Cyacetazid, pyrazolidone, virtue Fragrant aldehyde is raw material, catalyzes and synthesizes through base catalyst and obtains (Nan Wu, Xinnian Li, Yumei Wang and Daqing Shi,Journal of Chemical Research,2008,16-17;Tong-Shou Jin,Ai-Qing Wang,Zhan- Li Cheng,Jian-She Zhang,and Tong-Shuang Li,Synthetic Communications,2005,35, 137-143;Daqing Shi,Jie Mou,Qiya Zhuang,Lihui Niu,Nan Wu,and Xiangshan Wang, 2004,34,4557–4563;Tong-Shou Jin,Rui-Qiao Zhao,and Tong-Shuang Li,ARKIVOC,2006 (xi),176-182;Hassan Sheibani and Maryam Babaie,Synthetic Communications,2010, 40,257 265)), following equation (1)-(2).
Learn according to consulting literatures, about polysubstituted dihydropyran [2, the 3-c] pyrazol derivative of asymmetric synthesis chirality Thing there is presently no document report.
Accordingly, it would be desirable to develop polysubstituted dihydropyran [2, the 3-c] pyrazole derivatives of a kind of new method synthesis of chiral, And study their antibacterial activity.
Summary of the invention
The invention provides the conjunction of 1,4-dihydropyran (2,3-c) pyrazole derivatives of the good chirality of a kind of anti-microbial property One-tenth method.
A kind of Isosorbide-5-Nitrae-dihydropyran (2,3-c) pyrazole derivatives of chirality, structure is as shown in formula I:
In formula I, R is selected from hydrogen, methyl, methoxyl group, fluorine, chlorine or bromine, and Ph represents phenyl.
Isosorbide-5-Nitrae-dihydropyran (2,3-c) the pyrazole derivatives antibacterial action of these chiralitys is good, especially to golden yellow Fructus Vitis viniferae Coccus, streptococcus, escherichia coli, Pseudomonas aeruginosa suppression least concentration generally good than the compound of racemization.
Present invention also offers the synthetic method of Isosorbide-5-Nitrae-dihydropyran (2, the 3-c) pyrazole derivatives of described chirality, bag Include following steps:
In the presence of solvent, under the catalysis of Takemoto catalyst, pyrazolone derivative is reacted with Cyanoacetyl-Cyacetazid, Obtain 1,4-dihydropyran (2,3-c) pyrazole derivatives of chirality through post processing after reaction completely；
The structure of described pyrazolone derivative is as shown in formula II:
In formula II, R is as defined above.This synthetic method raw material is easy to get, easy and simple to handle.
Reaction equation is as follows:
The structural formula of described Cyanoacetyl-Cyacetazid is as follows:
As preferably, described solvent is toluene.Toluene has good dissolubility to raw material, and reacts in this solvent When carrying out, yield and ee value are the highest.
As preferably, described Takemoto catalyst, structure is as shown in formula IV:
Reaction temperature is 0 DEG C～20 DEG C, and the response time is 8-24 hour.
Described post processing includes: removal of solvent under reduced pressure, then through column chromatography.Wherein, the leacheate of column chromatography can be selected Petroleum ether and the mixed liquor of ethyl acetate.
In the present invention, the consumption of the substituted or unsubstituted pyrazolone derivative of reaction raw materials and Cyanoacetyl-Cyacetazid is the strictest Restriction, generally according to chemical reaction metering ratio react, it is also possible to be that one of which compound excess is reacted.
In the present invention, reaction dissolvent, the consumption of catalyst do not have strict restriction, can adjust according to the consumption of reaction raw materials Whole: when reaction raw materials is more, to increase reaction dissolvent and the consumption of catalyst, reduce reaction dissolvent and catalysis when reaction raw materials is less The consumption of agent.
The present invention finally provides 1,4-dihydropyran (2,3-c) pyrazole derivatives of described chirality as antifungal In application.Tests prove that, Isosorbide-5-Nitrae-dihydropyran (2, the 3-c) pyrazole derivatives of chirality is to staphylococcus aureus, hammer Bacterium, escherichia coli, Pseudomonas aeruginosa have certain inhibitory action.
As preferably, described antibacterial is used for suppressing escherichia coli；
Structure such as formula (3a), (3e) and (3g) institute of 1,4-dihydropyran (2,3-c) pyrazole derivatives of described chirality Show.
Now, bacteriostasis is good, and the minimum inhibitory concentration of each compound is low.
Present invention have the advantage that
The synthetic method of Isosorbide-5-Nitrae-dihydropyran (2, the 3-c) pyrazole derivatives of chirality of the present invention, its key problem in technology is to replace Or unsubstituted pyrazolone derivative and Cyanoacetyl-Cyacetazid are raw material, select cheap reaction dissolvent, select Takemoto catalyst, One kettle way is directly synthesized 1,4-dihydropyran (2,3-c) pyrazole derivatives of chirality；Having flexible reaction time, yield is higher, Solvent is cheap and easy to get, easy and simple to handle, applied widely many merits of Denging, is suitable for industrialized production.
1,4-dihydropyran (2,3-c) pyrazole derivatives of the chirality of the present invention is to staphylococcus aureus, streptococcus, big Enterobacteria, Pseudomonas aeruginosa all have certain inhibitory action, can use as antibacterial.
Accompanying drawing explanation
Fig. 1 is the simulation drawing of the transition state of the product of embodiment 1；
Fig. 2 is the ECD curve of the course of reaction by Gauss computed in software embodiment 1.
Detailed description of the invention
Embodiment 1
Reaction tube at 5mL adds pyrazolone derivative 2a(0.10mmol), Cyanoacetyl-Cyacetazid (0.10mmol) and such as formula (IV) Takemoto catalyst shown in (0.02mmol), is subsequently adding the toluene of 1ml, and mixture is little in temperature 15 DEG C stirring 12 Time.Then removal of solvent under reduced pressure, with petroleum ether and the mixed liquor of ethyl acetate (petroleum ether and ethyl acetate volume ratio are as 10:1) For leacheate carry out column chromatography obtain structural formula such as 3a chirality 1,4-dihydropyran (2,3-c) pyrazole derivatives 3a (31mg, Productivity 95%).
Reaction equation is as follows:
By the structure of Isosorbide-5-Nitrae-dihydropyran (2,3-c) the pyrazole derivatives 3a of chirality obtained above through nuclear magnetic resonance, NMR and High resolution mass spectrum is identified,1H NMR(400MHz,DMSO)δ(ppm)7.79(d,J=8.1Hz,2H),7.49(t,J= 7.9Hz,2H),7.37-7.22(m,8H),4.67(s,1H),1.77(s,3H);13C NMR(101MHz,CDCl3)δ(ppm) 159.50,145.36,143.94,143.67,137.60,129.41,128.61,127.86,127.13,126.24,120.11, 120.06,98.70,58.23,36.82,12.64;IR(KBr,cm-1)3471,3324,2198,1658,1592,1516,1491, 1457,1125,1065,753;ESI-HRMS:calcd.for C20H16N4O+Na351.1216,found351.1216.Show To 1,4-dihydropyran (2,3-c) pyrazole derivatives of chirality there is the structure shown in structural formula 3a.Meanwhile, compound 3a leads to Crossing chiral column OD post to record in high performance liquid chromatography, enantioselectivity is 99%ee.
By the simulation transition state of Fig. 1 it is recognised that (1) is to allow, the product obtained is R-configuration；(2) it is prohibited from , product is S-configuration.
It addition, Fig. 2 is the ECD curve of the course of reaction by Gauss computed in software, calculated by TD-DFT, ECD Curve mates with R-4a experimental data.The result of Fig. 1 and Fig. 2 illustrates that the absolute configuration of the product of embodiment 1 is as shown in formula 3a.
Embodiment 2
Reaction tube at 5mL adds pyrazolone derivative 2b(0.10mmol), Cyanoacetyl-Cyacetazid (0.10mmol) and such as formula (IV) Takemoto catalyst shown in (0.02mmol), is subsequently adding the toluene of 1ml, and mixture is little in temperature 15 DEG C stirring 12 Time.Then removal of solvent under reduced pressure, with petroleum ether and the mixed liquor of ethyl acetate (petroleum ether and ethyl acetate volume ratio are as 10:1) For leacheate carry out column chromatography obtain structural formula such as 3b chirality 1,4-dihydropyran (2,3-c) pyrazole derivatives 3b (32mg, Productivity 93%).
Reaction equation is as follows:
By the structure of chloro-for the 5-of chirality obtained above Isosorbide-5-Nitrae-dihydropyran (2,3-c) pyrazole derivatives 3b through nuclear-magnetism Resonance and high resolution mass spectrum are identified,1H NMR(600MHz,DMSO)δ(ppm)7.78(d,J=7.8Hz,2H),7.49(t,J =7.9Hz,2H),7.33-7.25(m,5H),7.17(t,J=8.8Hz,2H),4.72(s,1H),1.78(s,3H);13C NMR (151MHz,DMSO)δ(ppm)162.02,160.42,159.46,145.30,143.92,139.92,137.56,129.84, 129.78,129.42,126.28,120.07,115.42,115.28,98.54,58.07,36.00,12.64;IR(KBr,cm-1) 3454,3329,2203,1666,1597,1519,1445,1390,1126,1068,753;ESI-HRMS:calcd.for C20H15FN4O+Na369.1122, found369.1122. show 1,4-dihydropyran (2,3-c) pyrazol derivative of the chirality obtained Thing has the structure shown in structural formula 3b.Show that 1,4-dihydropyran (2,3-c) pyrazole derivatives of the chirality obtained has knot Structure shown in structure formula 3b.
Meanwhile, compound 3b is recorded in high performance liquid chromatography by chiral column OD post, and enantioselectivity is 90%ee.
Embodiment 3
Reaction tube at 5mL adds pyrazolone derivative 2c(0.10mmol), Cyanoacetyl-Cyacetazid (0.10mmol) and such as formula (IV) Takemoto catalyst shown in (0.02mmol), is subsequently adding the toluene of 1ml, and mixture is little in temperature 15 DEG C stirring 12 Time.Then removal of solvent under reduced pressure, with petroleum ether and the mixed liquor of ethyl acetate (petroleum ether and ethyl acetate volume ratio are as 10:1) For leacheate carry out column chromatography obtain structural formula such as 3c chirality 1,4-dihydropyran (2,3-c) pyrazole derivatives 3c (35mg, Productivity 97%).
Reaction equation is as follows:
By the structure of chloro-for 5-obtained above 1,4-dihydropyran (2,3-c) pyrazole derivatives 3c through nuclear magnetic resonance, NMR and High resolution mass spectrum is identified,1H NMR(600MHz,DMSO)δ(ppm)7.78(d,J=7.7Hz,2H),7.49(t,J= 7.9Hz,2H),7.41(d,J=8.4Hz,2H),7.30(t,J=8.0Hz,5H),4.72(s,1H),1.78(s,3H);13C NMR (151MHz,DMSO)δ(ppm)159.53,145.26,143.96,142.73,137.54,131.65,129.78,129.40, 128.60,126.28,120.06,98.24,57.74,36.12,12.64;IR(KBr,cm-1)3462,3325,2200,1661, 1595,1518,1445,1389,1122,1066,751;ESI-HRMS:calcd.forC20H15ClN4O+Na385.0827, Found385.0827. show that 1,4-dihydropyran (2,3-c) pyrazole derivatives of the chirality obtained has shown in structural formula 3c Structure.Show that 1,4-dihydropyran (2,3-c) pyrazole derivatives of the chirality obtained has the structure shown in structural formula 3c.With Time, compound 3c is recorded in high performance liquid chromatography by chiral column OD post, and enantioselectivity is 95%ee.
Embodiment 4
Reaction tube at 5mL adds pyrazolone derivative 2d(0.10mmol), Cyanoacetyl-Cyacetazid (0.10mmol) and such as formula (IV) Takemoto catalyst shown in (0.02mmol), is subsequently adding the toluene of 1ml, and mixture is little in temperature 15 DEG C stirring 12 Time.Then removal of solvent under reduced pressure, with petroleum ether and the mixed liquor of ethyl acetate (petroleum ether and ethyl acetate volume ratio are as 10:1) For leacheate carry out column chromatography obtain structural formula such as 3d chirality 1,4-dihydropyran (2,3-c) pyrazole derivatives 3d (29mg, Productivity 80%).
Reaction equation is as follows:
By the structure of Isosorbide-5-Nitrae-dihydropyran (2,3-c) the pyrazole derivatives 3d of chirality obtained above through nuclear magnetic resonance, NMR and High resolution mass spectrum is identified,1H NMR(600MHz,DMSO)δ(ppm)7.79(d,J=7.7Hz,2H),7.49(t,J= 8.0Hz,2H),7.39(t,J=7.7Hz,1H),7.36–7.30(m,5H),7.25(d,J=7.6Hz,1H),4.74(s,1H), 1.80(s,3H);13C NMR(151MHz,DMSO)δ(ppm)159.63,146.29,145.21,144.01,137.53, 133.24,130.55,129.39,127.68,127.23,126.74,126.32,120.15,119.99,98.03,59.84, 36.36,12.65;IR(KBr,cm-1)3472,3324,2194,1655,1591,1518,1445,1389,1125,1066,752; ESI-HRMS:calcd.for C20H15ClN4O+Na385.0827, found385.0825. show the 1,4-dihydropyran obtained (2,3-c) pyrazole derivatives has the structure shown in structural formula 3d.Meanwhile, compound 3d passes through chiral column in high performance liquid chromatography On record, enantioselectivity is 81%ee.
Embodiment 5
Reaction tube at 5mL adds pyrazolone derivative 2e(0.10mmol), Cyanoacetyl-Cyacetazid (0.10mmol) and such as formula (IV) Takemoto catalyst shown in (0.02mmol), is subsequently adding the toluene of 1ml, and mixture is little in temperature 15 DEG C stirring 12 Time.Then removal of solvent under reduced pressure, with petroleum ether and the mixed liquor of ethyl acetate (petroleum ether and ethyl acetate volume ratio are as 10:1) For leacheate carry out column chromatography obtain structural formula such as 3e chirality 1,4-dihydropyran (2,3-c) pyrazole derivatives 3e (27mg, Productivity 75%).
Reaction equation is as follows:
By the structure of Isosorbide-5-Nitrae-dihydropyran (2,3-c) pyrazole derivatives 3e obtained above through nuclear magnetic resonance, NMR and high-resolution Mass spectrum is identified,1H NMR(600MHz,DMSO)δ(ppm)7.78(d,J=7.8Hz,2H),7.49(t,J=7.9Hz,2H), 7.45(d,J=7.8Hz,1H),7.36-7.27(m,6H),5.15(s,1H),1.75(s,3H);13C NMR(151MHz,DMSO)δ (ppm)159.97,144.96,144.28,137.53,132.27,131.19,129.44,129.02,127.93,126.33, 120.07,119.764,119.755,97.80,59.85,20.84,12.39;IR(KBr,cm-1)3472,3324,2194, 1655,1591,1518,1445,1389,1125,1066,752;ESI-HRMS:calcd.for C20H15ClN4O+ Na385.0827, found385.0825. show that 1,4-dihydropyran (2,3-c) pyrazole derivatives obtained has structural formula 3e Shown structure.Meanwhile, compound 3e is recorded in high performance liquid chromatography by chiral column, and enantioselectivity is 80%ee.
Embodiment 6
Reaction tube at 5mL adds pyrazolone derivative 2f(0.10mmol), Cyanoacetyl-Cyacetazid (0.10mmol) and such as formula (IV) Takemoto catalyst shown in (0.02mmol), is subsequently adding the toluene of 1ml, and mixture is little in temperature 15 DEG C stirring 12 Time.Then removal of solvent under reduced pressure, with petroleum ether and the mixed liquor of ethyl acetate (petroleum ether and ethyl acetate volume ratio are as 10:1) For leacheate carry out column chromatography obtain structural formula such as 3f chirality 1,4-dihydropyran (2,3-c) pyrazole derivatives 3f (40mg, Productivity 99%).
Reaction equation is as follows:
By the structure of 1,4-dihydropyran (2,3-c) the pyrazole derivatives 3f of chirality obtained above through nuclear magnetic resonance, NMR and High resolution mass spectrum is identified,1H NMR(600MHz,DMSO)δ(ppm)7.78(d,J=7.7Hz,2H),7.54(d,J= 8.4Hz,2H),7.49(t,J=8.0Hz,2H),7.35-7.28(m,3H),7.23(d,J=8.4Hz,2H),4.71(s,1H), 1.79(s,3H);13C NMR(151MHz,DMSO)δ(ppm)159.17,144.91,143.60,142.79,137.16, 131.16,129.79,129.06,125.95,119.85,119.71,119.62,97.82,57.30,35.81,12.29;IR (KBr,cm-1)3452,3329,2203,1665,1596,1518,1447,1390,1126,1068,753,ESI-HRMS: calcd.for C20H15BrN4The 1,4-dihydropyran of the chirality that O+Na429.0321, found429.0321. show to obtain (2, 3-c) pyrazole derivatives has the structure shown in structural formula 3f.Meanwhile, compound 3f passes through chiral column OD post at high-efficient liquid phase color Recording in spectrum, enantioselectivity is 99%ee. embodiment 7
Reaction tube at 5mL adds pyrazolone derivative 2g(0.10mmol), Cyanoacetyl-Cyacetazid (0.10mmol) and such as formula (IV) Takemoto catalyst shown in (0.02mmol), is subsequently adding the toluene of 1ml, and mixture is little in temperature 15 DEG C stirring 12 Time.Then removal of solvent under reduced pressure, with petroleum ether and the mixed liquor of ethyl acetate (petroleum ether and ethyl acetate volume ratio are as 10:1) For leacheate carry out column chromatography obtain structural formula such as 3g chirality 1,4-dihydropyran (2,3-c) pyrazole derivatives 3g (33mg, Productivity 99%).
Reaction equation is as follows:
By the structure of bromo-for 5-obtained above Isosorbide-5-Nitrae-dihydropyran (2,3-c) pyrazole derivatives 39 through nuclear magnetic resonance, NMR and High resolution mass spectrum is identified,1H NMR(600MHz,DMSO)δ(ppm)7.78(dd,J=8.6,1.0Hz,2H),7.49(dd,J =8.5,7.6Hz,2H),7.34-7.29(m,1H),7.21(s,2H),7.16–7.11(m,4H),4.63(s,1H),2.28(s, 3H),1.78(s,3H);13CNMR(151MHz,DMSO)δ(ppm)159.39,145.36,143.90,140.73,137.60, 136.17,129.42,129.17,127.74,126.22,120.14,119.98,98.78,56.09,36.39,20.74, 12.67;IR(KBr,cm-1)3462,3345,2185,1653,1592,1516,1445,1388,1263,1073,759;ESI- HRMS:calcd.for C21H18N4O+Na365.1373, found365.1373. show the 1,4-dihydropyran of the chirality obtained (2,3-c) pyrazole derivatives has the structure shown in structural formula 3g.Meanwhile, compound 3g passes through chiral column OD post in efficient liquid phase Recording in chromatograph, enantioselectivity is 95%ee.
Embodiment 8
Reaction tube at 5mL adds pyrazolone derivative 2h(0.10mmol), Cyanoacetyl-Cyacetazid (0.10mmol) and such as formula (IV) Takemoto catalyst shown in (0.02mmol), is subsequently adding the toluene of 1ml, and mixture is little in temperature 15 DEG C stirring 12 Time.Then removal of solvent under reduced pressure, with petroleum ether and the mixed liquor of ethyl acetate (petroleum ether and ethyl acetate volume ratio are as 10:1) For leacheate carry out column chromatography obtain structural formula such as 3h chirality 1,4-dihydropyran (2,3-c) pyrazole derivatives 3h (35mg, Productivity 99%).
Reaction equation is as follows:
By the structure of bromo-for 5-obtained above 1,4-dihydropyran (2,3-c) pyrazole derivatives 3h through nuclear magnetic resonance, NMR and High resolution mass spectrum is identified,1H NMR(600MHz,DMSO)δ(ppm)7.78(dd,J=8.6,1.0Hz,2H),7.51–7.46 (m,2H),7.33–7.23(m,4H),6.83(ddd,J=17.5,6.3,4.7Hz,3H),4.66(s,1H),3.74(s,3H), 1.81(s,3H);13C NMR(151MHz,DMSO)δ(ppm)159.53,159.34,145.36,145.32,143.90, 137.58,129.75,129.40,126.23,120.10,120.05,120.02,113.93,111.98,98.54,58.01, 55.06,36.73,12.69;IR(KBr,cm-1)3398,3321,2192,1660,1595,1514,1456,1394,1250, 1073,1025,759;ESI-HRMS:calcd.for C21H18N4O2+ Na381.1322, found381.1320. show to obtain 1,4-dihydropyran (2,3-c) pyrazole derivatives of chirality has the structure shown in structural formula 3h.Meanwhile, compound 3h passes through hands Property post OD post records in high performance liquid chromatography, and enantioselectivity is 93%ee.
Embodiment 9: the anti-microbial property evaluation of sample segment
Document (Prashant T.Mistry, Nimesh R.Kamdar, Dhaval D.Haveliwala, and Saurabh K.Patel, J.Heterocyclic Chem., 2012,49,349.) report, breaks up compound in the middle part of this compounds To gram positive bacteria and gram negative bacteria inhibitory action, such as table 1.
Table 1 document (Prashant T.Mistry, Nimesh R.Kamdar, Dhaval D.Haveliwala, and Saurabh K.Patel, J.Heterocyclic Chem., 2012,49,349.) the partial racemization compound in minimum Mlc (MICs, μ g/mL)
To this, we are also according to the condition identical in document Isosorbide-5-Nitrae-dihydropyran (2,3-to synthesized chirality C) antibacterial activity of pyrazole derivatives has carried out preliminary study, and result is as shown in table 2.
The minimum inhibitory concentration (MICs, μ g/mL) of the different compound of table 2
Above it is demonstrated experimentally that Isosorbide-5-Nitrae-dihydropyran (2,3-c) pyrazole derivatives is to staphylococcus aureus, streptococcus, big Enterobacteria, Pseudomonas aeruginosa have certain inhibitory action, particularly 3a, and 3e, 3g are having extraordinary suppression to escherichia coli Effect.

Claims (2)

1. the application in preparing antibacterial of Isosorbide-5-Nitrae-dihydropyran (2, the 3-c) pyrazole derivatives of a chirality, described chirality Isosorbide-5-Nitrae-dihydropyran (2,3-c) pyrazole derivatives, shown in structure such as formula (3e) or (3g):
1,4-dihydropyran (2,3-c) pyrazole derivatives of chirality the most according to claim 1 is in preparing antibacterial Application, it is characterised in that described antibacterial is used for suppressing escherichia coli.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1084170A (en) * 1992-07-13 1994-03-23 出光兴产株式会社 Pyrazole derivatives
CN102153477A (en) * 2011-02-25 2011-08-17 苏州大学 Novel method for synthesizing chiral 4-nitryl-3, 5-diaryl cyclohexanone

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1084170A (en) * 1992-07-13 1994-03-23 出光兴产株式会社 Pyrazole derivatives
CN102153477A (en) * 2011-02-25 2011-08-17 苏州大学 Novel method for synthesizing chiral 4-nitryl-3, 5-diaryl cyclohexanone

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
Eco-friendly synthesis and biological evaluation of substituted pyrano[2,3-c]pyrazoles;Santhosh Reddy Mandha,等;《Bioorganic & Medicinal Chemistry Letters》;20120629;第22卷(第16期);5272-5278 *
Enantioselective synthesis of functionalized fluorinated dihydropyrano [2,3-c]pyrazoles catalyzed by a simple bifunctional diaminocyclohexane-thiourea;Hong-Fei Zhang, 等;《Chinese Chemical Letters》;20140124;第25卷(第4期);535-540 *
Nanosized magnesium oxide as a highly effective heterogeneous base catalyst for the rapid synthesis of pyranopyrazoles via a tandem four-component reaction;Maryam Babaie, 等;《Arabian Journal of Chemistry》;20100625;第4卷(第2期);159-162 *
Synthesis, characterization, and in vitro biological studies of some novel pyran fused pyrimidone derivatives;Prashant T. Mistry, 等;《Journal of Heterocyclic Chemistry》;20111231;第49卷(第2期);349-357 *

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